Cocaine receptor binding ligands

Abstract

PCT No. PCT/US91/05553 Sec. 371 Date Mar. 23, 1993 Sec. 102(e) Date Mar. 23, 1993 PCT Filed Aug. 9, 1991 PCT Pub. No. WO92/02260 PCT Pub. Date Feb. 20, 1992.3 beta -[4-iodophenyl]-tropan-2 beta -carboxylic acid methyl ester tartrate is a high affinity binding ligand for cocaine receptors in mammalian brains. It and its congeners may be employed for imaging and other brain scanning techniques that allow the determination of the presence of cocaine receptors, such as dopamine and serotonin transporters and the like.

We claim: 
     
       1. A compound of the formula below, where the broken line represents an optional chemical bond;   the iodo substituent may be at o, m, p, or multisubstituted and is a radioactive isotope;   R 1  =(CH 2 ) n  CH 3 , n=0-6; CH 2  CR 3  ═CR 4  R 5  (R 3 , R 4 , R 5  are each, independently, C 1  -C 6  alkyl); (CH 2 ) y  C 6  H 5  (y=1-6);   R 2  =CH 3 , C 2  H 5 , CH 3  (CH 2 ) 3 , (CH 3 ) 2  CH, C 6  C 5 , C 6  H 5  CH 2 , C 6  H 5  (CH 2 ) z  (z=1-6); and   X=pharmacologically acceptable anion. ##STR5##   
     
     
       2. The compound of claim 1, wherein said radioactive isotope is  123  I. 
     
     
       3. The compound of claim 1, wherein said radioactive isotope is  131  I. 
     
     
       4. The compound of claim 1, wherein said iodine moiety is in the para position. 
     
     
       5. The compound of claim 1, wherein at least one carbon atom thereof is  11  C. 
     
     
       6. The compound of claim 1, wherein said radioactive isotope is  125  I. 
     
     
       7. A compound of the formula ##STR6## wherein Sn(CH 3 ) 3  is ortho, meta or para, or multisubstituted and R 1  =(CH 2 ) n  CH 3  (n=0-6); CH 2  CR 2  ═CR 4  R 5  (R 3 , R 4 , R 5  are each independently C 1  -C 6  alkyl); (CH 2 ) y  C 6  H 5  (y=1-6); R 2  =CH 3 , C 2  H 5 , CH 3  (CH 2 ) 3 , (CH 3 ) 2  CH, C 6  H 5 , C 6  H 5  CH 2 , C 6  H 5  (CH 2 ) z  (z=1-6).   
     
     
       8. A method of assaying for the presence of cocaine receptors in the brain of a mammal, comprising administering a compound of claim 1 in a biologically acceptable carrier to said mammal, allowing said radioactively labeled compound to bind to cocaine receptors in the brain of said mammal, and scanning the brain of said mammal to determine the presence of radioactive iodine bound thereto, wherein the presence of radioactive iodine corresponds to a cocaine receptor site.   
     
     
       9. The process of claim 8, wherein said receptor is a dopamine receptor. 
     
     
       10. The process of claim 8, wherein said radioactive iodine isotope is  125  I,  123  I or  131  I. 
     
     
       11. The process of claim 10, wherein said radioactive iodine isotope is  125  I. 
     
     
       12. The process of claim 10, wherein said radioactive iodine isotope is  123  I. 
     
     
       13. A method of determining density and distribution of brain receptors in a patient, comprising administering an amount effective to effectuate binding to said receptors of the radioactively labeled compound of claim 1, in a pharmaceutically acceptable carrier, permitting said compound to bind to said receptors, and obtaining an image of the distribution and density of the compounds so bound. 
     
     
       14. The method of claim 13, wherein said compound is labeled with  123  I. 
     
     
       15. The method of claim 13, wherein said compound is labeled with  131  I. 
     
     
       16. A method for screening potential central nervous system-affecting drugs, comprising: administering a potential CNS-affecting drug to a mammal in an amount effective to provide for binding of said drug to cocaine receptors in said mammal, administering a compound of claim 1 to said mammal in amounts effective to provide for binding of said compound to cocaine receptors in said mammal, obtaining an image of the compound so bound, and comparing said image against a control image of the binding of said compound to said cocaine receptors in the absence of said drug.   
     
     
       17. A method of screening chemicals for neurotoxicity, comprising: administering a suspect neurotoxic chemical to a mammal in an amount effective to provide for interaction between nerve terminals in said mammal and said chemical, administering a compound of claim 1 to said mammal in amounts effective to provide for binding of said compound to cocaine receptors of said mammal, obtaining an image of the compound so bound, and comparing said image against a control image of the binding of said compound in the absence of said chemical.